Development of the skull is a complex process regulated by unique signaling mechanism that differ significantly from those required for the development of the axial (e.g. vertebral column, ribs, sternum) and appendicular (e.g. limbs, girdles) skeletons (Helms and Schneider, Nature 423: 326-331, 2003). While migrating neural crest cells differentiate into osteoblasts and chondrocytes to form the bones of the facial region, the cranial vault, which encapsulates the brain, is formed by direct differentiation of the paraxial mesodermal cells into osteoblasts without a cartilage intermediate (Jiang et al., Dev Biol 241: 106-116, 2002). To accommodate the rapidly growing brain during the early years of life, the cranial bones grow at their fibrous joints called sutures. These sutures contain immature, rapidly dividing osteogenic stem cells (Wilkie, Hum Mol Genet. 6: 1647-1656, 1997). It has been shown that signaling pathways that are activated by fibroblast growth factors (FGFs), bone morphogenetic proteins (BMPs) (Kim et al., Development 125: 1241-1251, 1998), transforming growth factor βs (TGF-βs) (Cohen, J Bone Miner Res 12: 322-331, 1997) and more recently noggin (Warren et al., Nature 422: 625-629, 2003) play an important role in suture development.
Craniosynostosis, the premature fusion of one or more sutures of the skull before the brain completes its growth, is one of the most common craniofacial abnormalities at birth caused by abnormal signaling in the sutural mesenchyine and occurs with a prevalence of approximately 1 in 2100-3000 births (Hehr and Muenke, Mol Genet Metab 68: 139-151, 1999). Hallmarks of craniosynostosis include abnormally shaped skull often associated with increased intracranial pressure, mental retardation, developmental delay, seizures and blindness that are caused by the constriction of the growing brain (Nuckolls et al., Cleft Palate Craniofac J 36: 12-26, 1999). It is now well established that gain of function mutations in members of the FGFR family of receptor tyrosine kinases (RTKs) cause syndromic craniosynostosis, which accounts for 15-20% of all known craniosynostosis disorders (Passos-Bueno et al., Hum Mutat 14: 115-125, 1999). For example, mutations in FGFR2 cause Crouzon, Apert, Pfeiffer, Jackson-Weiss and Beare-Stevenson syndromes. It is noteworthy that these individuals have a normal allele of Fgfr2c in addition to the mutated allele.
Crouzon syndrome is caused by mutations in the gene for fibroblast growth factor receptor-2 (FGFR2). Crouzon syndrome with acanthosis nigricans results from a mutation in the FGFR3 gene. Crouzon syndrome is characterized by cranial synostosis, hypertelorism, exophthalmos and external strabismus, parrot-beaked nose, short upper lip, hypoplastic maxilla, and a relative mandibular prognathism. Familial occurrence was noted by Crouzon (Bull. Mem. Soc. Med. Hop. Paris 33: 545-555, 1912) when he first described the syndrome. Subsequently, several investigators have demonstrated an autosomal dominant mode of inheritance, although sporadic cases have also been reported. There was marked variability in both cranial and facial manifestations of the syndrome. Two described sporadic cases also had syndactylism of both hands and feet, and may be more correctly labeled Vogt cephalodactyl). Cohen and Kreiborg (Clin. Genet. 41: 12-15, 1992) estimated that Crouzon syndrome represents approximately 4.8% of cases of craniosynostosis at birth. The birth prevalence was estimated to be 16.5 per million births.
There is strong evidence that Jackson-Weiss syndrome is caused by mutation in the gene encoding fibroblast growth factor receptor-2, although Roscioli et al. (Am. J. Med. Genet. 93: 22-28, 2000) reported an individual with what they considered to be the Jackson-Weiss syndrome, who had the FGFR1 pro252-to-arg mutation. Jackson et al. (J. Pediat. 88: 963-968, 1976) reported a syndrome of craniosynostosis, midfacial hypoplasia, and foot anomalies in an Amish kindred. It resembles Pfeiffer syndrome, in that there is enlarged great toes and craniofacial abnormalities. However, thumb abnormalities were not present. An autosomal dominant pedigree pattern with variable severity was observed in this disease. Indeed, phenotypic expression was so variable that the entire spectrum of the dominantly inherited craniofacial dysostoses and acrocephalosyndactylies (except classic Apert syndrome) was seen in the kindred. Apparent validation of the Jackson-Weiss syndrome was provided by reports of Escobar and Bixler (Birth Defects Orig. Art. Ser. XIII(3C): 139-154, 1977) and families observed by Cohen others. By 2-point linkage and haplotype analyses using 13 dinucleotide repeat markers on chromosome 10, Li et al. (Genomics 22: 418-424, 1994) showed that the Jackson-Weiss syndrome maps to the same region, 10q23-q26, as the Crouzon syndrome. In a study of the family in which the Jackson-Weiss syndrome was originally described, Jabs et al. (Nature Genet. 8: 275-279, 1994) discovered a mutation in the conserved region of the immunoglobulin IIIc domain of the gene for fibroblast growth factor receptor-2. The mutation was an ala344-to-gly missense mutation (A344G). Mutations in the FGFR2 gene have also been found in individuals with Crouzon syndrome. Heike et al. (Am. J. Med. Genet. 100: 315-324, 2001) studied a previously unrecognized branch of the original family reported by Jackson et al. (supra) and found the A344G mutation in FGFR2 in all affected members.
Pfeiffer syndrome was originally reported in 8 affected individuals in 3 generations, with 2 instances of male-to-male transmission (Pfeiffer, Z. Kinderheilk. 90: 301-320, 1964). The striking feature was broad, short thumbs and big toes. The proximal phalanx of the thumb was either triangular or trapezoid (and occasionally fused with the distal phalanx) so that the thumb pointed outward (i.e., away from the other digits). Evidence presented by Muenke et al. (Nature Genet. 8: 269-274, 1994) indicates that mutations in the gene for FGFR1 can cause familial Pfeiffer syndrome. The disorder can also be caused by mutation in the gene for FGFR2. The original family reported by Pfeiffer (supra) was of this type. In an individual with severe Pfeiffer phenotype, Tartaglia et al. (Hum. Genet. 99: 602-606, 1997) reported a de novo G-to-C transversion in exon IIIa of the FGFR2 gene, resulting in a Trp-to-Cys missense mutation at codon 290. Schaefer et al. (Am. J. Med. Genet. 75: 252-255, 1998) likewise found a Trp290-to-Cys mutation in a case of Pfeiffer syndrome type 2. A Trp290-to-Arg substitution was found by Meyers et al. (Am. J. Hum. Genet. 58: 491-498, 1996) in classic cases of Crouzon syndrome, whereas the Trp290-to-Gly mutation resulted in an atypically mild form of Crouzon syndrome (Park et al., Hum. Molec. Genet. 4: 1229-1233, 1995). Plomp et al. (Am. J. Med. Genet. 75: 245-251, 1998) reported 5 unrelated individuals with Pfeiffer syndrome type 2, two of the individuals showed the Cys342-to-Arg mutation.
Apert (Bull. Mein. Soc. Med. Hop. Paris 23: 1310-1330, 1906) defined a syndrome characterized by skull malformation (acrocephaly of brachysphenocephalic type) and syndactyly of the hands and feet of a special type (complete distal fusion with a tendency to fusion also of the bony structures). The hand, when all the fingers are webbed, has been compared to a spoon and, when the thumb is free, to an obstetric hand. A frequency of Apert syndrome of 1 in 160,000 births was estimated. There is strong evidence (Wilkie et al., Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome Nature Genet. 9: 165-172, 1995) that Apert syndrome results from mutations in the gene encoding FGFR2. Oldridge et al. (Am. J. Hum. Genet. 64: 446-461, 1999) analyzed 260 unrelated individuals with Apert syndrome and found that 258 had missense mutations in exon 7 of FGFR2, which affected a dipeptide in the linker region between the second and third immunoglobulin-like domains. Hence, the molecular mechanism of Apert syndrome is exquisitely specific. Studies of fibroblasts showed ectopic expression of the keratinocyte growth factor receptor (KGFR) domain of FGFR2, which correlated with the severity of limb abnormalities. This correlation provided genetic evidence that signaling through KGFR causes syndactyly in Apert syndrome. The missense mutations in exon 7 of the 258 patients were ser252 to trp in 172 patients, ser252 to phe in 1 patient, and pro253 to arg in 85 patients.
There is a need to develop new treatment methods for treating these related syndromes.